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In this paper, a CMOS relaxation oscillator with trimming and temperature compensation is presented for the on-chip multi-sensor systems which need MHz level frequency source. The proposed scheme uses a single current branch to charge the capacitor to generate the oscillation with voltage average feedback (VAF) circuit. Binary-weight current trimming array is adopted to reduce the frequency variation caused by the process variation under different process corners. A compensation calibration resistor array with Kelvin connection is utilized to improve the frequency variation with temperature. With the help of VAF, the frequency spread caused by the comparator delay is suppressed. This relaxation oscillator with a typical frequency of 13.4[Formula: see text]MHz is implemented in a standard 180[Formula: see text]nm CMOS process. Simulation results show that it achieves a frequency temperature coefficient of 28.3[Formula: see text]ppm/∘C from [Formula: see text]C to 125∘C and a 0.074%/0.1[Formula: see text]V frequency variation when supply voltage changes from 2.9 to 3.7[Formula: see text]V.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses around the world. Within-cell polarity is crucial to cell development and function maintenance, and some studies have found that it is closely related to cancer initiation, metastasis, and prognosis. The aim of our research was to find polarity-related biomarkers which improve the treatment and prognosis of HCC. For the knowledge-driven analysis, 189 polarity-related genes (PRGs) were retrieved and curated manually from the molecular signatures database and reviews. Meanwhile, in the data-driven part, genomic datasets and clinical records of HCC was obtained from the cancer genome atlas database. The potential candidates were considered in the respect to differential expression, mutation rate, and prognostic value. Sixty-one PRGs that passed the knowledge and data-driven screening were applied for function analysis and mechanism deduction. Elastic net model combing least absolute shrinkage and selection operator and ridge regression analysis refined the input into a 12-PRG risk model, and its pharmaceutical potency was evaluated. These findings demonstrated that the integration of multi-omics of PRGs can help us in untangling the liver cancer pathogenesis as well as illustrate the underlying mechanisms and therapeutic targets.

Long noncoding RNA HOTTIP (HOXA transcript at the distal tip) has recently been reported to have a role in the proliferation of various cancer cells, yet its role in cell migration, invasiveness, and the EMT (epithelial–mesenchymal transition) in breast cancer and the potential mechanisms remain unknown. Breast cancer cell lines MDA-MB-231 and MDA-MB-468 were transfected with shRNA (short hairpin RNA) that specifically targeting HOTTIP. We observed a remarkable decrease in migration and invasiveness in these two breast cancer cell lines after knock-down of HOTTIP by shHOTTIP. We also demonstrated that the EMT of these two breast cell lines was suppressed after HOTTIP knock-down, as evidenced by increased E-cadherin levels, and decreased levels of N-cadherin, Snail, and Twist. Moreover, HOTTIP silencing also suppressed tumor metastasis in nude mice in vivo. In addition, we found that the expression of β-catenin was significantly decreased in breast cancer cells after knock-down of HOTTIP. In a further rescue experiment using overexpression of β-catenin, the rates of cell migration, invasiveness, and EMT of HOTTIP-silenced breast cancer cells were promoted, disclosing a potential role of the Wnt–β-catenin signaling pathway in this process. Overall, we discovered the positive regulatory function of HOTTIP in the migration, invasiveness, and EMT of breast cancer cells, via regulating the Wnt–β-catenin pathway.

Oxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control and lipid metabolism in several species, including humans, monkeys, and rodents. However, OXT’s short half-life in circulation and lack of receptor selectivity limit its application and efficacy. In this study, we report an OXT peptide analog (OXTGly) that is potent and selective for the OXT receptor (OXTR). OXT, but not OXTGly, activated vasopressin receptors in vitro and acutely increased blood pressure in vivo when administered IP. OXT suppressed food intake in mice, whereas OXTGly had a moderate effect on food intake when administered IP or intracerebroventricularly. Both OXT (IP) and OXTGly (IP) improved glycemic control in glucose tolerance tests. Additionally, both OXT (IP) and OXTGly (IP) stimulated insulin, glucagon-like peptide 1, and glucagon secretion in mice. We generated lipid-conjugated OXT (acylated-OXT) and OXTGly (acylated-OXTGly) and demonstrated that these molecules have significantly extended half-lives in vivo. Compared with OXT, 2-week treatment of diet-induced obese mice with acylated-OXT [subcutaneous(ly) (SC)] resulted in enhanced body weight reduction, an improved lipid profile, and gene expression changes consistent with increased lipolysis and decreased gluconeogenesis. Treatment with acylated-OXTGly (SC) also resulted in a statistically significant weight loss, albeit to a lesser degree compared with acylated-OXT treatment. In conclusion, we demonstrate that selective activation of the OXTR pathway results in both acute and chronic metabolic benefits, whereas potential activation of vasopressin receptors by nonselective OXT analogs causes physiological stress that contributes to additional weight loss.

Objective: To provide comprehensive data to understand mechanisms of vascular endothelial cell (VEC) response to hypoxia/re-oxygenation. Methods: Human umbilical vein endothelial cells (HUVECs) were employed to construct hypoxia/re-oxygenation-induced VEC transcriptome profiling. Cells incubated under 5% O(2), 5% CO(2), and 90% N(2) for 3 h followed by 95% air and 5% CO(2) for 1 h were used in the hypoxia/re-oxygenation group. Those incubated only under 95% air and 5% CO(2) were used in the normoxia control group. Results: By using a well-established microarray chip consisting of 58 339 probes, the study identified 372 differentially expressed genes. While part of the genes are known to be VEC hypoxia/re-oxygenation-related, serving as a good control, a large number of genes related to VEC hypoxia/re-oxygenation were identified for the first time. Through bioinformatic analysis of these genes, we identified that multiple pathways were involved in the reaction. Subsequently, we applied real-time polymerase chain reaction (PCR) and western blot techniques to validate the microarray data. It was found that the expression of apoptosis-related proteins, like pleckstrin homology-like domain family A member 1 (PHLDA1), was also consistently up-regulated in the hypoxia/re-oxygenation group. STRING analysis found that significantly differentially expressed genes SLC38A3, SLC5A5, Lnc-SLC36A4-1, and Lnc-PLEKHJ1-1 may have physical or/and functional protein–protein interactions with PHLDA1. Conclusions: The data from this study have built a foundation to develop many hypotheses to further explore the hypoxia/re-oxygenation mechanisms, an area with great clinical significance for multiple diseases.

Background The shortage of quality-control materials caused by non-renewable utilization of rare disease samples is the key factor to limit the quality control of prenatal molecular diagnosis. This study aimed to prepare aneuploid amniocyte lines for the development of quality control cells for fluorescence in situ hybridization (FISH)-mediated detection of aneuploidy. Methods Recombinant SV40LTag-pcDNA3.1(-) vectors were transfected into 47,XY,+18 amniotic fluid cells with the use of liposomes. After culturing, these cells were mixed with primary amniocytes with the karyotype 46,XY to prepare four groups of chimeric quality control cells comprising recombinant cells with the karyotypes 47,XY,+18 and primary cells with 46,XY, with theoretical ratios of 47,XY,+18 cells at 5%, 10%, 20%, and 40%. Subsequently, the chimeric quality control cells were tested as clinical samples by three technicians to examine their feasibility for use as internal quality controls (IQC) for FISH detection. Results After being immortalized by the SV40 large T antigen gene (SV40LT), these aneuploid amniocytes can be cultured indefinitely to prepare chimeric quality control cells. The actual ratio of the 47,XY,+18 cells was identified by FISH to be 1.5 ± 1.1%, 10.3 ± 1.0%, 19.9 ± 0.4%, and 40.8 ± 0.3%, respectively, and the fluorescence signals of chromosomes 13, 18, 21, X, and Y in these cells were consistent with that of the primary cells. Conclusions The present study may resolve the shortage of quality control cells in the prenatal detection of chromosomal aneuploidy and may provide a foundation for IQC-based detection in FISH.

Objective: We describe a new method of immortalizing amniocytes with chromosome abnormalities to generate renewable resources for studying rare diseases. Methods: Three methods were investigated by randomly dividing 180 cases of adherent amniocytes into groups A, B, and C. Group A cells were digested with 0.25% trypsin for 10, 20, 30, 60, 90, and 120 mins. Group B and C cells were digested with 0.25% trypsin for 3–5 minutes. Group A and B cells were then transfected with PT67 cell-produced SV40LT. Group C digested cells underwent liposome-mediated SV40LT-transfection. Results: The percentage of clones immortalized by SV40LT transfection in groups A, B, and C were 18.3, 5.0, and 16.7%, respectively, after G418 screening. Group A produced a higher percentage of immortalized clones than did groups B and C, but only significantly differed from group B. The karyotypes and chromosome 13, 18, 21, X, and Y fluorescence signals in transfected cells of all groups were identical to those of the primary cells after passaging for 10–15 generations. Conclusions: The trypsin-mediated SV40LT transfection used in group A can be applied for routine establishment of amniocyte lines to obtain a renewable resource for the study of rare diseases and as quality control materials for prenatal diagnosis.

In this paper, we present an accurate analog decibel linear control circuit for variable gain amplifiers (VGAs). The proposed circuit features simple and effective dB-linear control for current steering VGAs. A novel temperature compensation circuit is also proposed for this VGA. Based on the proposed circuit design techniques, a wideband single stage VGA with accurate analog dB-linear gain control and temperature compensation is realized in Tower Jazz 0.18 μm SiGe BiCMOS technology. The measurement result shows the proposed VGA S21 gain is tunable from ź50 to +20 dB with a ź3 dB bandwidth of about 4.6 GHz. The measured IIP3 is from ź29 to ź8 dBm for maximum and minimum gain respectively and dissipates about 11 mA current from a single 1.8 V supply. The measured noise figure at maximum gain is about 8.5 dB when matched to 50 Ω and the VGA performance is insensitive to temperature variation when measured from ź40 to +80 °C.

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.

Background Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. Methods We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. Results This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. Significance Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.

Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed.

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

A new phase shifter based on injection-locked ring oscillator is proposed. By using a multi-stage phase generator with voltage-controlled injection locking technique, the proposed phase shifter is able to generate a flexible combination of coarse and fine-tuned phase delays over a wide range of operating frequencies while a small silicon area is maintained. Fabricated in a 0.18 µm RF CMOS process which only occupies 50 × 40 µm, a proposed three-stage phase shifter achieves flexible phase delays and a measured operating frequency up to 2 GHz with a maximum power consumption of 2 mW from a 1.8 V supply.

The underground powerhouse of a hydropower station is a typical large-span and high side wall cavern group. The stability analysis of high side wall and the rock between caverns is key for cavern design. Based on the process of excavation and anchorage of underground caverns, FLAC3D numerical modeling technique is used to dynamically analyze the distribution rules and variation features of the second stress field, displacement field plastic zones in the rock masses surrounding the caverns before construction of anchorage support and the loads carried by the supporting structures. The computation result shows that the opening's lay out, construction sequence and support parameters are rational.

EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.

This paper presents the rules of harmonic penetration in Zhengzhou harmonic voltage level. National standards limit the harmonic voltage distortion level in the buses, so study the UHV AC/DC hybrid system is significant to power grid. In order to find out the harmonic voltage level near Zhengzhou converter station, a method has been proposed in this paper, including the models of radiation power grid, load characteristics and converter station's AC filter. Finally, according to Zhengzhou converter station power frame sets up a detail model in the simulation software packages PSCAD/EMTDC to study the law of harmonic penetration.

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24 nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5 mg/kg) and dog (3 mg/kg) for over twelve hours.

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7 nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30 μM, and failed to inhibit human mPGES-2 at 62.5 μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62 mL/(min*kg)) and volume of distribution (Vd,ss = 1.6 L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

With the methods of compound-melting and high-temperature molding, PC/YAG:Ce fluorescent resin pieces were prepared. The transmittance of the prepared PC/YAG:Ce fluorescent resin in 500~800 nm reaches approximately 65% (0.71 mm thick, double sides polished). The fluorescent resin was characterized by XRD, SEM and PL. The X-ray diffraction (XRD) patterns demonstrated that the fluorescent resin was pure Y3Al5O12 phase. The scanning electron microscopy (SEM) images showed that YAG phosphor was distributed evenly in the fluorescent resin. The excitation spectra had a weak peak at 342 nm and a strong band at 448 nm. The broad emission peaks at about 532 nm can be attributed to 5d--4f transition of Ce3+ ions. Decay curves for the fluorescence of PC/YAG:Ce fluorescent resin show that the lifetime of the fluorescent resin was 61.5 ns. The luminous efficacy of the white LED packaged by the fluorescent resin and blue LED chip was 81.12 lm · W(-1) at 100 mA. All results above of PC/YAG:Ce fluorescent resin indicate a promising fluorescent material for white LEDs.

ADAMTS-4 (aggrecanase-1) is a metalloprotease that plays a role in aggrecan degradation in the cartilage extracellular matrix. In order to understand the regulation of ADAMTS-4 gene expression we have cloned and characterized a functional 4.5kb human ADAMTS-4 promoter. Sequence analysis of the promoter revealed the presence of putative binding sites for nuclear factor of activated T cells (NFAT) and Runx family of transcription factors that are known to regulate chondrocyte maturation and differentiation. Using promoter-reporter assays and mRNA analysis we have analyzed the role of chondrocyte-expressed transcription factors NFATp and Runx2 and have shown that ADAMTS-4 is a potential downstream target of these two factors. Our results suggest that inhibition of the expression/function of NFATp and/or Runx2 may enable us to modulate aggrecan degradation in normal physiology and/or in degenerative joint diseases. The ADAMTS-4 promoter would serve as a valuable mechanistic tool to better understand the regulation of ADAMTS-4 expression by signaling pathways that modulate cartilage matrix breakdown.